Project Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is an established curative strategy for a variety of malignant and non malignant hematologic disorders. Although significant advances have been made; 30-50% of patients will still die from either relapse, infections or complications of graft versus host disease. The primary objective of Project 6 is to conduct a series of clinical trials (CTs) testing novel approaches that address major challenges to the success of alloHCT. The CTs included in this project address one of two specific aims. SA1 will test and develop novel cellular approaches to prevent relapse or enhance immune reconstitution post alloHCT. This aim will be addressed by two CTs. CT1 is ?A randomized, phase 2 study of donor allograft CD34+ selection versus TCR-??+ cell depletion GVHD prophylaxis for patients undergoing allogeneic hematopoietic cell transplantation for high risk hematologic malignancies? in which we will compare immune reconstitution between a novel graft manipulation strategy that depletes only alpha/beta T cells and our well established CD34 selection procedure. The goal of this study is to demonstrate that the novel graft manipulation strategy will result in a more robust immune reconstitution with reduction in the risk of infections and improved HCT outcomes. CT2 is a Phase I Trial Using In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the CD19 Antigen in B-cell Malignancies. SA2 will ascertain the impact of gastrointestinal (GI) microbiota on HCT outcomes. This aim will be addressed through the performance of two CTs. CT3 addresses microbiome preservation through rationale antibiotic use (Open-label phase II randomized trial of empiric treatment of fever and neutropenia (F&N) with piperacillin-tazobactam vs. cefepime in recipients of unmodified allogeneic HCT). CT4 will test the ability of 3rd party fecal microbiota transplants to restore microbiota diversity (Phase II Trial of 3rd Party Fecal Microbiota Transplantation (FMT) in Recipients of Allogeneic HCT). More than 9000 allo-HCTs will be performed in the United States this year. The two SAs with the six proposed clinical trials in this project address the most common causes of treatment failure. The three trials exploring the impact of the GI microbiome on HCT outcomes will either devise new strategies to prevent or remediate loss of GI microbiome diversity while at the same time increasing our understanding of the mechanisms by which bacteria or their products can cause or prevent harm after an allo-HCT. The three clinical trials proposed will test novel cellular strategies to address relapse and immune reconstitution. These strategies will allow us to develop less toxic and more effective allo-HCT regimens in the future.